1. Field of the Invention
The present invention relates to pharmaceutical compositions comprising prasugrel and a cyclodextrin derivative, and methods of making and using the same, for example, to treat disorders and diseases that are therapeutically responsive to prasugrel.
2. Background of the Invention
Platelets play a central role in the pathogenesis of atherothrombosis and in the formation of thrombi following coronary angioplasty, with and without stent implantation. Platelets initially adhere at sites of vascular injury, atherosclerotic plaque rupture, balloon angioplasty, and stenting. Platelet activation following these interactions results in the release of adenosine diphosphate (“ADP”), thromboxane A2, and other mediators. Released ADP promotes platelet activation via the G-protein linked P2Y1 and P2Y12 purinergic receptors leading to further platelet activation, aggregation, and other platelet functions, such as platelet shape change, secretion, and the development of pro-coagulant and pro-inflammatory activities. Activated platelets are recruited to sites of coronary plaque rupture and intra-arterial stenting, thereby forming aggregates that may lead to platelet-rich thrombi, vascular occlusion, tissue ischemia, and myocardial necrosis in what is collectively known as Acute Coronary Syndrome (“ACS”). The term ACS is a pathophysiological continuum progressing from ischemic chest pain with sudden onset and worsening, to ischemia severe enough to cause irreversible myocardial damage detected with cardiac biomarkers without persistent ST-segment elevation, to total occlusion of the culprit coronary artery with persistent ST-segment elevation, resulting in myocardial necrosis and elevated biomarkers. ACS occurs in a diverse global population and has a significant socioeconomic impact as subjects require hospitalization, rehabilitation, and often suffer subsequent ischemic events.
Options for the initial management of ACS include pharmacotherapy alone or an early invasive strategy with percutaneous coronary intervention (“PCI,” with or without coronary stenting) or coronary artery bypass grafting (CABG) as guided by the results of coronary angiography. The current American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend an early invasive strategy for ACS subjects with intermediate to high-risk features. Pharmacotherapy includes both anticoagulant and anti-platelet drugs. The current standard of care for subjects with ACS includes dual anti-platelet therapy with aspirin and thienopyridine in both the acute and chronic phases of treatment. This therapy improves outcome in subjects with ACS and those undergoing PCI; the high risk of early stent-associated thrombosis is substantially reduced by dual antiplatelet therapy. Ticlopidine and clopidogrel are the two currently approved thienopyridines. Due to its once-daily dosing regimen, clopidogrel is the predominantly prescribed therapeutic agent to treat subjects suffering from ACS.
Several potential limitations of clopidogrel therapy have been identified despite the loading dose of clopidogrel. This includes marked inter-individual variability in platelet inhibition and relatively slow onset of action. An association between thrombotic complications following PCI and poor antiplatelet response to the approved standard clopidogrel dosing regimen (loading dose (“LD”) 300 mg and maintenance dose (“MD”) 75 mg) has been suggested. Further, it has been shown that “nonresponsiveness” to a clopidogrel 600 mg LD is a strong predictor of stent thrombosis in subjects receiving drug-eluting stents, and in addition, that residual platelet aggregation above the median is associated with a 6.7-fold increased risk of major adverse cardiac events (death, myocardial infarction and target vessel revascularisation) at 1 month follow-up in subjects undergoing elective PCI. These observations suggest the possibility that higher and more consistent levels of platelet inhibition may improve clinical outcome in subjects with ACS undergoing PCI.
Prasugrel is a thienopyridine ADP receptor antagonist that can be orally or parenterally administered, and has the chemical name 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate (chemical formula: C20H20FNO3S; molecular weight 373.44 g/mol). Clinical testing of prasugrel has utilized a racemic mixture of the hydrochloride salt, which is a white to light brown crystalline solid that is slightly hygroscopic. Prasugrel hydrochloride is soluble to slightly soluble at pH 1-4, very slightly soluble at pH 5 and practically insoluble at pH 6-7. The pKa value of prasugrel hydrochloride is 5.1. Prasugrel is also known to demonstrate polymorphism.
Prasugrel undergoes in vivo metabolism via hydrolysis by carboxylesterases and then multiple cytochrome P450 enzymes to form an active metabolite that irreversibly inhibits platelet activation and aggregation mediated by the P2Y12-receptor. Once bound, a platelet is inhibited for its remaining lifespan. After prasugrel dosing is stopped, a return to baseline levels of platelet aggregation will occur as new platelets are formed, a process that typically occurs over about 7-10 days after treatment is stopped.
Non-clinical studies indicate that, with respect to inhibiting ex vivo platelet aggregation and in vivo thrombus formation, prasugrel was approximately 10-fold to 100-fold more potent than clopidogrel and ticlopidine, respectively. Prasugrel compositions, dosage forms, and methods of treatment using the same are known. See, e.g., U.S. Pat. Nos. 5,288,726, 5,436,242 and 6,693,115, U.S. Patent Pub. Nos. 2008/0108589 and 2008/0176893, and WO 2004/098713, WO 2006/138317 and WO 2008/073759, which are incorporated herein by reference in the entirety. Clinical data in healthy subjects has confirmed the greater platelet inhibition and more consistent response to prasugrel compared to clopidogrel. While the active metabolites of prasugrel and clopidogrel resulted in similar levels of platelet inhibition in vitro, the amount of each active metabolite generated in vivo differs significantly: a prasugrel loading dose of 60 mg results in approximately a 50-fold greater exposure, on a per milligram basis, to its active metabolite compared to a clopidogrel loading dose of 300 mg.
Compositions comprising clopidogrel and a cyclodextrin derivative are known. See, e.g., U.S. Pat. No. 5,989,578, WO 2008/072836, WO 2008/134600 and WO 2008/134601, which are incorporated herein by reference in the entirety.
Prasugrel has completed at least one clinical trial relating to treating subjects suffering from acute coronary syndromes who have undergone a percutaneous coronary intervention or for whom a percutaneous coronary intervention is planned. See, e.g., Wiviott, S. D. et al., N. Engl. J. Med. 357:2001 (2007). Acute coronary syndrome includes heart attacks and unstable angina (chest pain). Prasugrel has demonstrated a reduction in the combined rate of death from cardiovascular causes and nonfatal myocardial infarction, as well as nonfatal stroke compared to clopidogrel. However, subjects administered prasugrel have also exhibited an increased rate of serious bleeding events. In the clinical trial, three subgroups had less efficacy and greater absolute levels of bleeding than the overall treatment group, resulting in a reduced net clinical benefit or in clinical harm. The risk of bleeding related adverse effects was most evident in patients with a history of stroke or transient ischemic attack before enrollment, the elderly (subjects 75 years of age and older), and subjects having a body mass less than 60 kg. It was postulated that the increased risk of bleeding in elderly subjects and subjects having a body mass less than 60 kg may have been due to increased levels of the active metabolite, arising from an altered disposition to the drug and/or a smaller body size.